N-glycolylarsanilate salts of chloroquine



ijnited States i atent ZJMJMS Free Patented July 25, 1955N-GLYCGLYLARSANILATESALTS on .cnronooomn No Drawing Application August10, 1953, Serial No. 373,452

6 Claims. (Cl. 260-271) This invention relates to derivatives, of,7-chloro-4- (4-diethylamino-l-methylbutylamino)quinoline (chloroquine)and N glycolylarsanilic acid .(4-glycolylamidophenylarsonic acid). quinedi-(N-glycolylarsanilate) and chloroquine tri-(N- glycolylarsanilate.)properties.

Of the antiamebic drugs presently available, those that are mosteffective in clearing Endamoeba histolytica from the intestine areineffective against extraintestinal forms of, the disease. Conversely,those drugs that are effective in the'treatment of hepatic amebiasis arepoor agents against intestinal amebiasis. Chloroquine, or 7chlorol-(4-diethylarnino-l-rnethylbutylamino)quinoline, has been foundto be a highly effective drug for the treatment of hepatic amebiasis, aswell as malaria; however, it is relatively ineffective againstintestinal amebiasis.

We have now found that N-glycolylarsanilate salts of chloroquine arehighly effective as intestinal amebacides. This effectiveness has beendemonstrated against E. criceti infections in hamsters and E.histolytica infections in humans. Thus, the compounds of our inventionare dual-acting agents for concurrent treatment of both intestinal andextraintestinal forms of amebiasis.

The compounds of our invention were prepared by treating a solution ofN-glycolylarsanilic acid in a polar solvent with the appropriatequantity of chloroquine. Thus, treatment of 2 moles ofN-glycolylarsanilic acid with 1 mole of chloroquine yields chloroquinedi-(N- glycolylarsanilate) and treatment of 3 moles ofN-glycolylarsanilic acid with 1 mole of chloroquine yields chloroquinetri -(N-glycolylarsanilate). This process for preparing our compoundscan be nm at room temperature, although preferably at a highertemperature, e. g., effected by use of steam bath, because of theresultant greater rate of reaction. The chloroquine-N-glycolylarsanilatesalts were isolated preferably by evaporation of the reaction solvent;alternatively, the salts can be obtained by precipitating them from thereaction mixture with an excess of the appropriate solvent, such asacetone.

The invention is further illustrated by the following examples but it isnot limited thereto.

EXAMPLE 1 Chloroquine tri-(N-glycolylarsanilate) To a hot solution of g.of N-glycolylarsanilic acid (this sample contained 12.72% water) in 450ml. of 80% ethanol was added 15.2 g. of7-chloro-4-(4-diethylaminol-methylbutylamino)quinoline. The hot solutionwas treated with decolorizing charcoal and filtered. The solvent wasthen removed by distillation in vacuo. The residue was stirred in about300 ml. of acetone for about one hour. The acetone was then decanted andreplaced by a fresh supply of acetone. By continued stirring andtrituration with a glass rod, if necessary, the taffy-like materialsolidified. The solid was collected, dried at 60 C. overnight and thenat 100 C. to constant weight.

In particular, it relates to chlorowhich have valuable amebacidal Thisdried product, chloroquine tri-(N-glycolylarsani late), a whitecrystalline solid, melted with decomposi tion at 158160. (con).

Anal.Calcd. for CmHzeClNs-3CaH1oAsNO5zChl0r0- quine, 27.85;N-glycolylarsanilic acid, 72.15.

F0und.-Chloroquine, 25.70 (dry basis); N-glycolylarsanilic acid by As,72.85 (dry basis); loss'in weight at C., 1.19. Y

Chloroquine tri-(N-glycolylarsanilate) is soluble in water to the extentof at least 20%, the pH of a 1% solution being 3.7. When such an aqueoussolution is adjusted with 0.1 N sodium hydroxide to a pH of 7.0, thereis no precipitation.

The efficacy of chloroquine-tri-(lJ-glycolylarsanilate)..

in clearing intestinal amebiasis of hamsters (Crice t us auratus) wasdetermined as follows:

such a manner that 1.0 cc. contained the desired daily dose. Hamsters(100-110 g.), which were infected with Er damoeba criceti, weremedicated by stomach tube twice daily for four days. autopsied andscrapings from the ceca wereexamined microscopically for the presence oftrophozoites. Three microscopic examinations from diiferent areas of thececum were made before an animal was reported as being free from amebicinfection. The combined results of several tests are tabulated in TableI.

*In two of the four hamsters po itive for amebae at this dose level,very few amebae were found.

In addition to the above tests in hamsters, chloroquinetri-(N-glycolylarsanilate) has been found effective as an arnebacidalagent in humans, a study having been carried out in four patients. Twoof these patients have had acute exacerbations of amebiasis over 15-yearperiods and were put on a regimen of 750 mg. of chloroquinetri-(N-glycolylarsanilate) three times daily for one week. Follow-upstool examinations at the end of four weeks showed both patients to befree of amebae. Subsequent stool examinations were still negative for E.hist'olytz'ca at the end of thirteen weeks. The remaining two patientshad acute dysentery and were placed on the same regimen. Stools taken atthe end of medication and at the end of four weeks were negative forpathogenic amebae.

EXAMPLE 2 Chloroquine di-(N-glycolylarsanilate) This preparation wascarried out following the procedure described in Example 1 using 6.3 g.of N-glycolylarsanilic acid (contained 12.72% water), 65 cc. of 80%ethanol and 3.19 g. of 7-chloro-4-(4-diethylamino- 1methylbutylamino)quinoline. There was thus obtained 7.5 g. (86%) yieldof the product, chloroquine di-(N-glycolylarsanilate), M. P. 158161 C.with decomposition (when immersed in bath at C.).

Anal.-Calcd. for C1sH2eClN3-2CsH1oAsNO5: Chloroquine, 36.75; As, 17.25.

Found.-Chloroquine, 34.40; As, 18.08.

Preparations of f chloroquine tri-(N-glycolylarsanilate) "at varyingconcentrations were made up in 10% autoclaved gelatin in On the fifthday they were In another run the product when dried at about 60 C.retained about 8% water of hydration and melted at 85.4-88.4 C. (cor.)with decomposition.

Chloroquine di-(N-glycolylarsanilate) is soluble in water to the extentof at least 20%, the pH of a 1% solution being 5.2. When such an aqueoussolution is adjusted with 0.1 N sodium hydroxide to a pH of 7.0, thereis. no precipitation.

When tested for amebacidal activity in hamsters according to theprocedure described above in Example 1, chloroquinedi-(N-glycolylarsanilate) was found to be active as summarized in TableII.

We claim:

1. A compound selected from the group consisting of the diandtri-(N-glycolylarsanilate) salts of 7-chloro- 4-(-4-diethylarninol-methylbutylamino quinoline.

2. 7 chloro-4-(4-diethylamino-l-methylbutylamino)- quinolinedi-(glycolylarsanilate).

3. 7 ch1oro-4-(4-diethylamino-l-methylbutylamino)- quinoline tri-(N-glycolylarsanilate) 4. The process for the preparation of a compoundselected from the group consisting of the diand tri-(N-glycolylarsanilate) salts of7-chloro-4-(4-diethylaminol-methyloutylamino)quinoline, which comprisestreating a solution containing a member of the group consisting of twoand three moles of N-glycolylarsanilic acid in a polar solvent with 1mole of 7-chloro-4-(4-diethylaminol-methylbutylamino) quinoline.

5. The process for the preparation of 7-chloro-4-(4-diethylamino-l-methylbutylamino)quinoline di (N-glycolylarsanilate)which comprises treating a solution containing 2 moles ofN-glycolylarsanilic acid in a polar solvent with 1 mole of7-chloro-4-(4-diethylamino-lmethylbutylamino quinoline.

6. The process for the preparation of 7-chloro-4-(4- diethylamino-lmethylbutylamino)quinoline tri-(N-glycolylarsanilate) which comprisestreating a solution containing 3 moles of N-glycolylarsanilic acid in apolar solvent with 1 mole of 7-chloro-4-(4-diethylamino-1-methylbutylamino) quinoline.

References Cited in the file of this patent UNITED STATES PATENTSDelrner Apr. 13, 1954 OTHER REFERENCES Surrey et al., J. A. C. S. 68:1136, January 18, 1946.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THE DI- ANDTRI-(N-GLYCOLYLARSANILATE) SALTS OF7-CHLORO4-(4-DIETHYLAMINO-1-METHYLBUTYLAMINO)QUINOLINE.